March 2019 digital v1

esearch
COMBATING MALARIA: THE GENOMIC WAY
Genome-wide analysis of the malarial parasite provides clues on potential drug targets
ANIKET PRATAPNENI
New methods of treatment and
prevention have emerged to treat
malaria from the growing field
of genetics. The first of these methods
involves targeting the Plasmodium
genome. By conducting genome-wide
analyses, researchers have been able
to identify core genes of the malarial
parasite that offer targets for new drugs.
One of the most important of these
studies – and possibly indicative of the
future course of the disease treatment
– was conducted at the University of
Melbourne. The researchers used genetic
analysis and basic biology to discover
what could be an instrumental chink in
malaria’s armour of mutability.
Atovaquone is an anti-malarial
drug that was not under use for fear
of the development and spread of
resistance. However, the study showed
that although malaria parasites can
develop resistance to atovaquone, but
they cannot spread it. The mutation that
makes it possible to resist atovaquone
also render it impossible for the parasite
to survive the subsequent step of its life
cycle – entering a mosquito. And since
malaria cannot be transferred from one
person to another, the atovaquoneresistant
parasite cannot spread. This
illuminates a new strategy for managing
drug resistance. The mutation pathway
that results in this genetic quandary can
be targeted by drug developers while
creating new drugs.
‘Partner’ drugs
Researchers at the Wellcome Sanger
Institute and the University of South
Florida used a new, specialized
technique – piggyBac-transposon
insertional mutagenesis – to inactivate
random Plasmodium falciparum genes
and incorporated a newly developed
sequencing tool to identify the relative
importance of each gene in terms of
survival. They found that around fifty
percent (over 2,600 out of 5,400) of
the genes were essential for its growth
and propagation in erythrocytes – a list
of 2,600 targets for drug developers.
In addition, approximately 1,000 of
those 2,600 targets are common to all
Plasmodium species, and although their
exact functions are currently unknown,
their status as integral genes make them
DRUGS TARGETING GENES
WOULD BE EXTREMELY
EFFECTIVE AS ‘PARTNER’
DRUGS, WORKING IN TANDEM
WITH ARTEMISININ
potential targets for anti-malarial drugs.
Many of these genes were also found to
be involved in a proteasome pathway
that is responsible for degrading proteins
in the cell, which is thought to be
linked to artemisinin resistance. Thus,
drugs targeting these genes would be
extremely effective as ‘partner’ drugs,
working in tandem with artemisinin.
Extinction by gene drive?
The second of these new methods
involves targeting the Anopheles
genome. In a recent study, genetic
engineers used CRISPR/Cas9 to render
a population of Anopheles gambiae
mosquitos – Africa’s primary malariaspreading
mosquito species – incapable
of producing offspring within twelve
generations. Based on the results of
further trials using this tool, it could
be the first to be able to eliminate
an entire species of disease-carrying
mosquitos. The tool used to create
such a groundbreaking effect was a
gene drive. These use the CRISPR/Cas9
‘scissor’ enzyme to insert themselves
into an organism’s genome at specific
loci. This gene drive in particular exploits
a recessive Anopheles gene called
doublesex. If a female mosquito inherits
two copies of the broken doublesex
gene, it develops like a male, which
are incapable of biting – and therefore
infecting – humans. Any mosquito that
inherits only one copy of the exploited
gene will develop normally. The gene
drive was designed to circumvent the
natural laws of inheritance. Normally,
if a parent carries two different alleles
of a gene, the offspring will have a
50% chance of inheriting either one.
However, with the doublesex gene
drive, more than 95% of the offspring
inherited the exploited gene, allowing
it to spread through the population
much faster. Once all the members of
a generation carried two copies of the
gene drive – which took between 8 and
12 generations in the study – none of
the mosquitos were capable of laying
eggs or biting, forcing the population to
die out without biting other organisms.
The gene drive creates the prospect of
causing the extinction of malaria-carrying
species, which could eventually result in
the extinction of malaria itself.
Author is a student at
TISB, Bangalore. He
interned at Professor
Bobby Kasthuri’s lab at
the University of Chicago
and will be pursuing
undergraduate studies
in the field of molecular
biology.
80 / FUTURE MEDICINE / March 2019